Multiple Myeloma in a Young Adult with Renal Involvement

Abstract Multiple myeloma (MM) results from malignant plasma cell disorder. It represents approximately 10% of hematological malignancies and it is typically diagnosed in the elderly with a median age of 70 years and has a steep increase in incidence with advancing age. N Engl J Med. 2004, 1860; Clin Interv Aging. 2020, 619. The incidence of MM has been increasing over time, mostly due to population aging. Mayo Clin Proc. 2010, 225 However, certain MMs are diagnosed at young age even under 40 years old (2%). Leuk Lymphoma. 1998, 493; Blood. 2010, 5501. We report a case of a MM in a thirty‐four‐year‐old woman whose circumstance of discovery was acute kidney failure.

. We report a case of a MM in a thirty-four-year-old woman whose circumstance of discovery was acute kidney failure.

K E Y W O R D S
cast nephropathy, early-onset multiple myeloma, prognosis, renal biopsy, survival, treatment response albumin (37.6 g/L), serum β2 microglobulin (29.4 mg/L), and LDH level (488 mmol/L). Our patient was detected to have t (4:14) at Interphase fluorescence in situ hybridization (iFISH). Therefore, our patient was staged R-ISS II. For the symptomatic treatment component, she had erythropoietin analogs; she required a total of 3 sessions of conventional hemodialysis with blood transfusion, notably before the kidney biopsy. When treating the causative disease, she received courses of Bortezomib (1.3 mg/ m2) -Thalidomide (100 mg/day) -Dexamethasone (40 mg/ day) according to the schedule of 6 cycles of 21 days each. Our patient presented a favorable clinical and biological evolution with an improvement in renal function (creatinine 212 pmol/l), anemia (Hb 12 g/dl), gamma globulin at 10.5 without a peak and seric free light chains ratio (kappa = 63, Lambda = 43, kappa/lambda = 1.45) after at least 1 year of admission to our department ( Figure 3). The disease status in pre-transplant was complete remission. On January 2018, she received an autologous stem cells transplant (ASCT) after conditioning with Bortezomib and Melphalan. Since then, she has evolved favorably and her renal function was stable (last serum creatinine in March 2021: 192 μmol/L).

| DISCUSSION
Characteristics and prognosis of young patients with MM are not well known, and available literature comes from case reports and small series. [9][10][11][12][13][14][15][16] Hewell et al. have described the first documented cases of young patients with MM and reported a frequency of 1%. 9 Blade et al. reviewed the records of 3278 patients treated for MM at the Mayo clinic between 1956 and 1992 and concluded that the incidence of MM in patients younger than 40 and 30 years was 2.2% and 0.3%, respectively. 10 The clinical and biological characteristics of MM among young patients are as the same as in elderly patients in most series, there seem to be some specific aspects. A multicentric study found that men are more affected than women (sex ratio: 2/1). 17 Higher incidence of the ISS 1 disease in younger patients with MM was also reported. 11,13,17 In this context, some studies demonstrated that the prognosis in individuals diagnosed with MM before 40 years of age may be better than in older MM patients. 10,14 Several hypotheses have been ahead such as the lack of comorbidities in this population and the eligibility for ASCT. Another finding is that the presence of an elevated serum concentrations of F I G U R E 1 Monoclonal gamma peak at proteins electrophoresis in our patient. LDH. 13,14 However, it is still unclear if the elevated level of LDH can be considered a specific feature of early-age MM, however, it was mentioned in our patient. Usha et al. reported 14 cases of MM in patients <40 years old out of 178 cases, 10 of them had an IgG myeloma as was noticed in our patient. 18 The second particularity of our observation is that renal impairment was not only part of the clinical presentation but also revealing of MM diagnosis. The pathogenesis of renal injury in MM is multifactorial. Excess FLC filtration and overburdening of proximal resorptive capacity, with subsequent uromodulin interactions in distal tubules, may precipitate cast formation, inducing tubulointerstitial damage and fibrogenesis. 19 Cast nephropathy is the commonest cause of renal injury in MM, followed by hypercalcemia. 20 Monoclonal proteins deposit along tubular basement membranes leading to a tubulointerstitial nephropathy, as it was the case in our patient. Few studies have investigated the most common types of MM in the young population but it has been reported that light-chain disease (LCD) patients were slightly younger than IgA and IgG patients but older than IgD patients. 21 As for our patients, It was a MM with IgG Lambda. The Kidney Disease Improving Global Outcomes (KDIGO) clinical practice guidelines for Acute kidney injury (AKI) recommend biopsy "if the cause of AKI is not clear after careful evaluation, especially in patients in whom prerenal and postrenal causes of AKI have been excluded, and the cause of intrinsic AKI is unclear. It is particularly useful when clinical assessment, urinalysis, and laboratory investigation suggest diagnoses other than sepsis, or ischemic or nephrotoxic injury" 22 Renal biopsy is the key to confirm the association between a monoclonal protein and kidney disease. The spectrum of renal lesions that are seen in patients with myeloma includes "myeloma kidney," or cast nephropathy; light-chain (AL) amyloidosis; monoclonal Ig deposition disease (MIDD); and, less frequently, cryoglobulinemic glomerulonephritis and proliferative glomerulonephritis. 23 Autopsy studies in patients with myeloma found cast nephropathy in 30%-50%, light-chain deposition disease in 2%-3%, and amyloidosis in 4%-5% of cases. 24,25 In one study, 24 acute tubular necrosis was seen in 34% of cases. Renal biopsy is the key to confirm the association between a monoclonal protein and kidney disease. The incidence of hypercalcemia and renal failure was documented in 2 large retrospective analyses but, did not confirm that younger age at the diagnosis predisposed to hypercalcemia and renal failure in MM patients. 12,13 Renal injury is a pejorative predictor of overall survival and increases the risk of additional complications in MM patients. 26 Early diagnosis and treatment are crucial to control and reverse renal failure. The use of new markers of renal failure in MM is a promising direction and should be considered in the future. 27 In a large study of patients diagnosed with myeloma before age 40, 28 at 5 years, relative survival compared with same age-and sex-matched individuals was 83.5%, and estimated standardized mortality ratio was 69.9 confirming that MM dramatically shortens the survival of young patients despite an extended survival after diagnosis. So far, our patient has presented a good prognosis.

| CONCLUSION
Little is known about the disease characteristics and prognosis of these patients. The diagnosis of myeloma may result F I G U R E 3 Kinetics of the various biological parameters throughout the follow-up and chemotherapy treatment in our patient. from the workup of unexplained renal disease. This diagnosis must be considered even at a young age since it involves the patient's prognosis, especially in the presence of an unexplained renal failure which should lead to renal biopsy.

AUTHOR CONTRIBUTIONS
The first author made substantial contributions to acquisition and interpretation of data and writing the manuscript. The second author has been involved in revising it critically for important intellectual content. The third author contributed through the examination of histopathological lesions in renal biopsy and providing the photos. The last author has given final approval for the version to be published.

ACKNOWLEDGMENTS
We are indebted to Dr S. Barbouch active and thoughtful contribution to the management of the patient. We also thank Dr Rim Goucha for having performed and interpreted the patient renal biopsy published with written consent of the patient.

FUNDING INFORMATION
No funding to declare.